Reductive cleavage of the exocyclic ester of UK-2A or its derivatives and products formed therefrom

ABSTRACT

A process comprising reacting compound GF-I with a reducing agent to form compound GF-II wherein Y is selected from the group consisting of H, benzyl, substituted benzyl, CH 2 OC 1-8  alkyl, CH 2 OC 3-8  cycloalkyl, allyl, tetrahydropyranyl, tetra-hydrofuranyl, substituted tetrahydropyranyl, substituted tetra-hydrofuranyl, Si(C 1-4  alkyl) 3 , and Si(Ph) x (C 1-4  alkyl) 3-x  where x is equal to 1, 2 or 3; and wherein said process is conducted: (a) in the presence of a reducing agent; (b) in the presence of an aprotic solvent; and (c) under reaction conditions; is provided. Additionaly, novel compounds produced therefrom are provided text:

This application claims the benefit of Provisional Application No.60/308,939, filed Jul. 31, 2001.

FIELD OF THE INVENTION

This invention is related to the field of processes used to cleave anester from a compound, and is also related to the field of compoundsthat may be used as fungicides, and is also related to the field ofcompounds that can be used to produce compounds that can be used asfungicides.

BACKGROUND OF THE INVENTION

UK-2A is a natural product having the following formula.

UK-2A is described in M. Ueki, et al. J Antibiot. 1996, 49, 639. Whilethis compound has certain properties that make it useful in a variety offields, currently, it is being investigated as a starting point formaking compounds that have efficacy in the fungicide area.

SUMMARY OF THE INVENTION

It is an object of this invention to provide a process to reductivelycleave the exocyclic ester of UK-2A or its derivatives and to producenovel compounds, which are useful intermediates in the synthesis ofbiologically active materials.

In accordance with this invention a process is provided. Said processcomprises reacting compound GF-I with a reducing agent to form compoundGF-II. Additionally, novel compounds produced therefrom are claimed.

For the purposes of this application the following terms have thefollowing meanings. The term “Ph” means phenyl. The term “Me” meansmethyl. The term “EtOAc” means ethyl acetate. The term “ppm” refers toparts per million. The term “psia” refers to pounds per square inchabsolute. The term “m.p.” refers to melting point. Throughout thisdocument, all temperatures are given in degrees Celsius (° C.), allpercentages are weight percentages, all melting points are uncorrected,unless otherwise stated.

DETAILED DESCRIPTION OF THE INVENTION

In reaction GR-I

Y is selected from the group consisting of H, benzyl, substitutedbenzyl, CH₂OC₁₋₈ alkyl, CH₂OC₃₋₈ cycloalkyl, allyl, tetrahydropyranyl,tetrahydrofuranyl, substituted tetrahydropyranyl, substitutedtetrahydrofuranyl, Si(C₁₋₄ alkyl)₃, and Si(Ph)_(x)(C₁₋₄ alkyl)_(3-x)where x is equal to 1, 2, or 3.

The term “substituted benzyl” means a benzyl group having one or moresubstituents. The substituents on the ring of the substituted benzyl arecalled “Ring Substituents”. Ring Substituents are selected from thegroup consisting of halo (F, Cl, and Br), C₁₋₈ alkoxy, C₂₋₈ alkenoxy,C₅₋₈ cycloalkoxy, and phenyloxy. The substituents on the methylenecarbon of the substituted benzyl are called “Methylene Substituents”.Methylene Substituents are C₁₋₃ alkyl. Each of the Ring and MethyleneSubstituents that have one or more hydrogens, may have one or more ofsuch hydrogens replaced with a halogen (F, Cl, and Br).

The terms “substituted tetrahydropyranyl” and “substitutedtetrahydrofuranyl” mean a tetrahydropyranyl or tetrahydrofuranylsubstituted with one or more substituents selected from the groupconsisting of halo (F, Cl, and Br), C₁₋₈ alkyl, C₁₋₈ alkoxy, C₂₋₈alkenoxy, C₅₋₈ cycloalkoxy, and phenyloxy. Each of these substituentsthat have one or more hydrogens, may have one or more of such hydrogensreplaced with a halogen (F, Cl, and Br).

Examples of silyl compounds include, but are not limited to,Si(t-Bu)Me₂, Si(Ph)Me₂, SiEt₃, and SiMe₃.

Currently, Y is preferably H or benzyl, with H being most preferred.

A reducing agent is used in reaction GR-I. Currently, any hydride withthe correct reduction potential to remove the ester may be used.Suitable examples of such hydrides are: (1) R¹R²HAl; (2) R¹R²R³AlHM; and(3) R¹R²R³BHM. In these hydrides R¹, R², R³ are independently selectedfrom the group consisting of H, C₁₋₈ alkyl, hetero C₁₋₈ alkyl, C₁₋₈alkoxy, and hetero C₁₋₈ alkoxy. The term “hetero” in hetero C₁₋₈ alkyland hetero C₁₋₈ alkoxy means a molecular structure containing 1-8 carbonatoms and 1-3 oxygen or sulfur atoms in the main chain of the molecularstructure. Examples of these molecular structures include, but are notlimited to, CH₃CH₂OCH₂CH₂—, CH₃OCH₂CH₂OCH₂CH₂—, and CH₃CH₂SCH₂—, M isselected from the group consisting of Na, Li, K, Ca, Zn. Currently, itis preferred to use diisobutylaluminum hydride. Currently, it ispreferred to have an excess of reducing agent to GF-I. It is morepreferred to have about 3 to about 4 moles of reducing agent to GF-Idepending upon Y. If Y is H it is preferred to have about 4 moles ofreducing agent per mole of GF-I. If Y is not H it is preferred to haveabout 3 moles of reducing agent per mole of GF-I.

The reaction is conducted in an aprotic solvent. The solvent can beselected from the group consisting of tetrahydrofuran, 1,4-dioxane,dichloromethane, toluene, di(C₁₋₈ alkyl) ether, C₅₋₈ alkanes, C₃₋₈cycloalkanes, 1,2-dichloroethane, benzene, substituted benzene, glyme,diglyme, or mixtures thereof. The term “substituted benzene” means abenzene substituted with one or more substituents selected from thegroup consisting of halo (F, Cl, and Br), C₁₋₃ alkyl, C₁₋₈ alkoxy, C₂₋₈alkenoxy, C₅₋₈ cycloalkoxy, and phenyloxy.

The reaction conditions comprise a temperature from about −80° C. toabout 50° C., preferably about −25° C. to about 25° C. Currently,pressure is not considered to be critical and a pressure from aboutambient to about 50 psia may be used. In general, it is best to run thereaction with the components substantially in the liquid state.

After the reaction is substantially complete, the product GF-II isrecovered from the reaction mixture. This can be accomplished by firstquenching the reaction by adding water, alcohol, ester, ketone, or analdehyde (examples include, but are not limited to, methanol, ethylacetate, and acetone). This is followed by using a mineral acid(examples include, but are not limited to, HCl and H₂SO₄) to promoteseparation of the reaction mixture components. This is then followed byextracting compound GF-II into an organic solvent. Examples of suchorganic solvent include, but are not limited to, EtOAc and methylenechloride.

EXAMPLES

These examples are provided to illustrate the invention. They are notmeant to be construed as limiting the invention.

Natural product UK-2A (1) or the benzyl ether (2) were subjected todiisobutylaluminum hydride in methylene chloride (CH₂Cl₂) at reduced orambient temperature to provide the des-isobutyryl derivatives 3 and 4.

Preparation of (3S, 6S, 7R,8R)-8-benzyl-3-({[3-(benzyloxy)-4-methoxypyridin-2-yl]carbonyl}amino)-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl2-methylpropanoate (2)

Benzyl bromide (0.233 mol, 27.7 mL) was added to a solution of NaI(0.097 mol, 14.5 g) in acetone (1 L). Natural product UK-2A (1) (0.194mol, 100 g) was added followed by powdered K₂CO₃ (0.388 mol, 53 g) andthe mixture stirred vigorously overnight. The mixture was diluted withCH₂Cl₂ (500 mL) and washed with H₂O (2×500 mL). The organic layer wasdried (MgSO₄), and concentrated in vacuo. Recrystallization(EtOAc/hexane) gave 95.5 g (79%) of 2 as an off-white solid (m.p.169-170° C.) which contained ˜6.5% N-benzylated product (LC-MS). ¹H-NMRand MS (M+1 605) were consistent for the title compound (2). Thecompound was used in the next step without further purification. TheN-benzylated by-product could be removed from the mixture prior torecrystallization by filtration of the crude reside through a plug ofsilica gel (30% acetone/hexane as the eluent).

Preparation of N-[(3S, 7R, 8R,9S)-7-benzyl-8-hydroxy-9-methyl-2,6-dioxo-1,5-dioxonan-3-yl]-3-(benzyloxy)-4-methoxypyridine-2-carboxamide(4)

Diisobutylaluminum hydride (1.0 M in CH₂Cl₂, 24.8 mmol) was addeddropwise to a −78° C. solution of (2) (8.27 mmol, 5.0 g) in CH₂Cl₂ (40mL). The mixture was stirred an additional 15 min, quenched with EtOAc(200 mL) and warmed to ambient temperature. Hydrochloric acid (2N, 100mL) was added slowly and stirred vigorously for 15 min. The layers wereseparated and the organic layer dried (MgSO₄) and concentrated in vacuo.The residue was purified by chromatography (1% acetic acid/acetone) togive 1.54 g (35%) of 4 as a glassy, white solid, m.p. 110-114° C. ¹H-NMRand MS (M+1 535) were consistent with the desired product.

Preparation ofN-[(3S,7R,8R,9S)-7-benzyl-8-hydroxy-9-methyl-2,6-dioxo-1,5-dioxonan-3-yl]-3-hydroxy-4-methoxypyridine-2-carboxamide(3)

Diisobutylaluminum hydride (1.0 M in CH₂Cl₂, 23.3 mmol) was addeddropwise to a 20° C. solution of natural product UK-2A (1) (5.8 imol,3.0 g) in CH₂Cl₂ (60 mL). The mixture was stirred an additional 15 minand quenched with EtOAc (10 mL). Hydrochloric acid (2N, 100 mL) wasadded slowly and stirred vigorously for 15 min. The layers wereseparated and the organic layer dried (MgSO₄) and concentrated in vacuoto give 1.82 g (70%) of 3 as a foamy, light yellow solid. ¹H NMR (300MHz, CDCl₃): δ 11.82 (s, 1H), 8.63 (d, J=8.2 Hz, 1H), 8.01 (d, J=5.2 Hz,1H), 7.32-7.20 (m, 5H), 6.89 (d, J=5.2 Hz), 5.35 (m, 1H), 5.16 (m, 1H),4.86 (m, 1H), 3.96 (s, 3H), 3.76 (t, J=9.4 Hz, 1H), 3.62 (m, 1H), 3.25(m, 1H), 3.02 (m, 1H), 2.77 (m, 1), 1.51 (d, J=6.3 Hz, 3H); ¹³C NMR(MHz, CDCl₃): δ 173.2, 170.2, 169.4, 155.8, 149.2, 141.1, 138.8, 130.3,129.2, 129.0, 127.0, 110.1, 77.6, 77.2, 65.4, 56.5, 54.4, 50.3, 35.4,18.7 ppm; IR (KBr pellet): 3370 (br), 2966, 1751, 1654, 1529, 1453,1263, 1045, 801 cm⁻¹; Exact Mass: n/z calcd. for C₂₂H₂₄N₂O₈[M]⁺=444.1533, found 444.1513.

1. A process comprising reacting compound GF-I with a reducing agent toform compound GF-II

wherein Y is selected from the group consisting off H, benzyl,substituted benzyl, CH₂OC₁₋₈ alkyl, CH₂OC₃₋₈ cycloalkyl, allyl,tetrahydropyranyl, tetra-hydrofuranyl, substituted tetrahydropyranyl,substituted tetrahydrofuranyl, Si(C₁₋₄ alkyl)₃, and Si(Ph)_(x)(C₁₋₄alkyl)₃ where x is equal to 1, 2, or 3; and wherein said process isconducted: (a) in the presence of a reducing agent; (b) in the presenceof an aprotic solvent: and (c) at a temperature from about −80° C. toabout 50° C.
 2. A process according to claim 1 wherein Y is selectedfrom the group consisting of H and benzyl.
 3. A process according toclaim 1 wherein said reducing agent has a general formula selected fromthe group consisting of R¹R²HAl, R¹R²R³AlHM or R¹R²R³BHM, and whereinR¹, R², R³ are independently selected from the group consisting of H,C₁₋₈ alkyl, hetero C₁₋₈ alkyl, C₁₋₈ alkoxy, and hetero C₁₋₈ alkoxy, andwherein the term “hetero” in hetero C₁₋₈ alkyl and hetero C₁₋₈ alkoxymeans a molecular structure containing 1-8 arbon atoms and 1-3 oxygen orsulfur atoms in the main chain of the molecular structure, and wherein Mis selected from the group consisting of Na, Li, K, Ca, and Zn.
 4. Aprocess according to claim 1 wherein said reducing agent isdiisobutylaluminum hydride.
 5. A process according to claim 1 wherein anexcess of reducing agent to GE-I is used.
 6. A process according toclaim 1 wherein about 3 to about 4 moles of reducing agent to GF-I isused.
 7. A process according to claim 1 wherein Y is H and about 4 molesof reducing agent per mole of GE-I is used.
 8. A process according toclaim 1 wherein Y is not H and about 3 moles of reducing agent per moleof GF-I is used.
 9. A process according to claim 1 wherein said aproticsolvent is selected from the group consisting of tetrahydrofuran,1,4-dioxane, dichioromethane, toluene, di(C₁₋₈ alkyl) ether, C₅₋₈alkanes, C₃₋₈ cycloalkanes, 1,2-dichloroethane, benzene, substitutedbenzene, glyme, diglyme, or mixtures thereof.
 10. A process according toclaim 1 wherein said aprotic solvent is selected from the groupconsisting of dichioro methane toluene or mixtures thereof.
 11. Aprocess according to claim 1 wherein said reaction conditions comprise atemperature from about −25° C. to about 25° C.
 12. A process accordingto claim 1: (1) wherein Y is selected from the group consisting of H andbenzyl; (2) wherein said reducing agent has a general formula selectedfrom the group consisting of R¹R²Hal, R¹R²R³AlHM or R¹R²R³BHM, whereinR¹, R², R³ are independently selected from the group consisting of H,C₁₋₈ alkyl, hetero C₁₋₈ alkyl, C₁₋₈ alkoxy, and hetero C₁₋₈ alkoxy, andwherein the term “hetero” in hetero C₁₋₈ alkyl and hetero C₁₋₈ alkoxymeans a molecular structure containing 1-8 carbon atoms and 1-3 oxygenor sulfur atoms in the main chain of the molecular structure, andwherein M is selected from the group consisting of Na, Li, K, Ca, andZn; (3) wherein an excess of reducing agent to GF-I is used; (4) whereinsaid aprotic solvent is selected fro the group consisting oftetrahydrofuran, 1,4-dioxane, dichloromethane, toluene, di(C₁₋₈ alkyl)ether, C₅₋₈ alkanes, C₃₋₈ cycloalkanes, 1,2-dichloroethane, benzene,substituted benzene, glyme, diglyme, or mixtures thereof.
 13. A processaccording to claim 1: (1) wherein Y is selected from the groupconsisting of H and benzyl; (2) wherein said reducing agent isdiisobutylaluminum hydride; (3) wherein about 3 to about 4 moles ofreducing agent to GF-I is used; (4) wherein said aprotic solvent isselected from the group consisting of dichloromethane, toluene, ormixtures thereof.
 14. A compound GF-II

wherein Y is selected from the group consisting of H, benzyl,substituted benzyl, CH₂OC₁₋₈ alkyl, CH₂OC₃₋₈ cycloalkyl, allyl,tetrahydropyranyl, tetrahydrofuranyl, substituted tetrahydropyranyl,substituted tetrahydrofuranyl, Si(C₁₋₄ alkyl)₃, and Si(Ph)_(x)(C₁₋₄alkyl)_(3-x) where x is equal to 1, 2, or
 3. 15. A compound according toclaim 14 wherein Y is selected from the group consisting of H andbenzyl.
 16. A compound according to claim 14 wherein Y is H.
 17. Acompound according to claim 15 wherein Y is benzyl.